Acta Scientific Pharmaceutical Sciences (ISSN: 2581-5423)

Volume 3 Issue 12 December 2019

Review Article

Process Validation Protocol of Granules for Oral Administration

Sayef Shahriad Ripon1*, Akhlaque Hasan Khan2, Samir Kumar Bakshi1, Tareq2, Kshitish Chandra Das1 and Mostafa
Kamal Parvez2
1
Mundipharma (Bangladesh) Pvt. Ltd, Mirzapur, Gazipur, Bangladesh
2
Genvio Pharma Limited, Bagan, Trishal, Mymensingh, Bangladesh
*Corresponding Author: Sayef Shahriad Ripon, Mundipharma (Bangladesh) Pvt. Ltd, Mirzapur, Gazipur, Bangladesh.
Received: November 05, 2019; Published: November 19, 2019
DOI: 10.31080/ASPS.2019.03.0441

Abstract
To ensure that the pharmaceutical product is being produced with its consistent quality standard, process validation is a very
effective tool. It establishes documented evidence to ensure a high degree of assurance that specific process will consistently produce
a product meeting its predetermined specifications and quality requirements. Process validation is a cGMP requirement for finished
products and to standardize the method used in establishing process validation studies, a process validation protocol is developed.
Based on the protocol, once the process validation is done, a complete process validation report will be prepared which will aid in
preparing a complete BMR and BPR for manufacturing and packaging of pharmaceutical products.
Keywords: Process Validation; Protocol; CGMP; BMR; BPR

Introduction control, quality attributes, acceptance criteria, change control,

Process (Prospective) validation aims to gain full understand-
ing of the manufacturing process on the production equipment
expected to be routinely used. This is achieved by establishing pa-
rameters to be used to operate within a state of control. Once the
validation of process is completed, a Batch Manufacturing Record
(BMR) to be finalized to use in routine manufacturing. Any varia-
tion mode to this BMR should be made in accordance with change
control procedure [1-5].
Purpose
The purpose of this protocol is to cover the process validation
activities for the manufacturing of Granules for oral administra-
tion. Based on the Technology Transfer set Parameters, three con-
secutive successful batches will be manufactured and finalized the
critical process parameters for the batch manufacturing.
Scope
This protocol is applicable to validate Granules for Oral Admin-
istration under specified manufacturing conditions. This protocol
shall define the responsibilities of personnel involved, equipment
used, raw material details, critical process parameters, in-process
documentation to be carried out during Process Validation study of
Granules for Oral Administration.
Product details
Product Name, Generic Name, Dosage Form, Product Category,
Product Description, Label Claim, Packaging, Batch No., Mfg. Date,
Exp. Date, Batch Size, Shelf Life, Product Code No.
Documentation
Check the following documents: Process Validation Protocol,
Master Formulation Card, Master Packaging Card, Batch Manufac-
turing Record, Batch Packaging Record, Standard Test Specifica-
tion, Standard Testing Procedure and Process Validation Report
etc.
Validation team
The process validation team is comprised of at least one rep-
resentative from all concern departments i.e. QA, QC, Production,
Warehouse and Maintenance Department and the validation activ-
ity will be led by Head of Validation or Head of QA.

Citation: Sayef Shahriad Ripon., et al. “Process Validation Protocol of Granules for Oral Administration”. Acta Scientific Pharmaceutical Sciences 3.12
(2019): 37-42.
Process Validation Protocol of Granules for Oral Administration

38

Responsibilities • Finished product sampling and testing will be carried out as

Department Activities
Quality To prepare validation protocol.
Assurance
To ensure the activities to be
followed as per the approved
protocol.
To withdraw the samples as
per sampling program.
To organize the training and
impart the training before
validation.
To co-ordinate the validation
activity.
To approve the protocol.
Quality To analyze the samples.
Control
To check the results
Production To review validation protocol.
To ensure performance of
activities as per protocol.
To organize the activity.
To review the report.
Maintenance To provide required services.
Head, Plant To authorized the protocol.
Table 1
per respective established procedure.
Responsibility
Officer • During execution of the validation batches, Batch Manufactur-
ing Record (BMR) and Batch Packaging Record (BPR) will be
completed as per respective procedure.
List of equipments
Make a list of all the machine, equipment and instrument to be
used during process validation activity of respective products. The
list should include; equipment ID, Model Number, Manufacturer,
Capacity, Material of Construction, Qualification status and the re-
spective Operating SOP
Head, QA
Analyst Location of validation activity
Mention the name and address of the place where the process
Head, QC
validation activity will be done.
Officer/Head,
PR
Master manufacturing formula
Master Manufacturing formula includes Name of the ingredi-
Head, PR
ents with their compendia name, Quantity/sachet (mg), Quantity/
Batch (Kg) and the category and use of each ingredient.
Officer/Head,
MN
Identification of critical process variables parameter
GM, Plant
Probable causes that may affect final products

Training
The training on the protocol shall be imparted to all the person-
nel involved in the process validation activity (QA, QC, Production,
Warehouse and Maintenance).

Validation methodology
• The validation will be performed on three consecutive
batches of the same batch size following the established
manufacturing process described in this validation proto-
col.

• The validation study will be carried out at extreme and op-

timum values within the accepted ranges of critical process
parameters. All critical parameters shall be monitored and
documented for reviewed.

• In process sampling will be carried out as per the sampling

plan given in this protocol.
Figure 1: Probable Causes.

Citation: Sayef Shahriad Ripon., et al. “Process Validation Protocol of Granules for Oral Administration”. Acta Scientific Pharmaceutical Sciences 3.12
(2019): 37-42.
Process Validation Protocol of Granules for Oral Administration

39

Critical process parameter Sampling, test parameters and acceptance criteria

Sampling plan and sampling location
Stage: Manufacturing Process Parameter
Manufacturing Area Temperature Wear nose mask and surgical hand gloves before Sampling. Take
Manufacturing Area RH out 75g sample as shown in the table from Top, Middle and Bot-
Ampere Load tom of the blender, in a clean polyethylene bag. Label the samples
Total Drying Time with Product Name, Batch No., Stage, Area, Time and Date. Send the
Moisture Content (By KFT) samples to QC for analysis. Ensure that no further mixing is done
Stage: Blending Mixing Time in QC.
Bulk Density (Tapped)
Sieve Analysis (Fines)
Weight of the Granules
Stage: Filling and Filling Area Temperature
Sealing Filling Area RH
Sealing Temperature (Bottom Sealer)
Sealing Temperature (Vertical Sealer)
Sealing Temperature (Top Sealer)
Machine Speed
Auger Speed
Auger Count
Leak Test o Sampling Points
Quality of Batch Printing
T1: Top 1, T2: Top 2, T3: Top 3, M1: Middle 1, M2: Middle 2, M3:
Packaging Area temperature
Middle 3, B1: Bottom 1, B2: Bottom 2, B3: Bottom 3, B4: Bottom 4
Packaging Area RH
Table 2 Figure 2: Octagonal Blender.

Stage: Granulatation
Drying
Sampling Sampled Test To Be
Sl. Sampling Points Frequency
Location Quantity Carried Out
1. FBD Bowl After drying from One sample from each Tray (Top, Middle and 1gX6 Moisture Content
Top, Middle and Bottom)
Bottom layer of FBD
Bowl.
Drying
1. Tray Dryer After drying from One sample from each Tray (Top two, Middle 1gX6 Moisture Content
Top, Middle and Bot- two and Bottom Two).
tom layers.
Blending
1. Octagonal After drying from 10 samples each after 05 minutes, 08 , minutes 1 g X 10 Assay of individual sample.
Blender Top (T1, T2 and T3), and 10 minutes (Triplicate)
Middle (M1, M2 and
M3) and Bottom
Trays (B1, B2, B3 and
B4).
Composite Sample. After completion of mixing. 60 g Bulk analysis as per
specifications, bulk density
and sieve analysis.

Stage: Filling/Sealing And Packaging

Citation: Sayef Shahriad Ripon., et al. “Process Validation Protocol of Granules for Oral Administration”. Acta Scientific Pharmaceutical Sciences 3.12
(2019): 37-42.
Process Validation Protocol of Granules for Oral Administration

40

1. Sachet During sachet filling At Machine Speed 60 Sachet/Min and Sealing 5 Appearance, Physical Veri-
Filling and and sealing operation Temp. (Bottom) 1350C, Sealing Temp. (Vertical) 15 fication, Leak test, Average
Sealing (Auger speed 900- 1500C, Sealing Temp. (Top) 1750C. sachets Fill and Fill Variation.
Machine 1000 rpm, Auger
At Machine Speed 70 Sachet/Min and Sealing 15
count 2000-2500
Temp. (Bottom) 1350C, Sealing Temp. (Vertical) sachets
No.)
1500C, Sealing Temp. (Top) 1750C.
At Machine Speed 80 Sachet/Min and Sealing 15
Temp. (Bottom) 1350C, Sealing Temp. (Vertical) sachets
1500C, Sealing Temp. (Top) 1750C.
Initial, Middle and End at Optimum speed and 15 sachets Appearance, Average Mass,
sealing Temperature and Full, Half and Low each Uniformity of Mass, Quality
Hopper. of Batch Printing, Leak Test
and Assay.
2. Packing From Packing Belt As per SOP 21 Complete analysis as per
Room sachets specification.

Table 3

Specifications Sifting details

Bulk specification
Operation/Parameter Std. Specification
Bulk specification should include description, identification,
Room Cleaning Should be clean
solubility in water, pH, moisture content and assay of granules.
Equipment Cleaning Should be clean
Finished product specification Equipment Calibration Should be calibrated
Bulk specification should include description, identification, av- Sifting Area Temperature Not more than 250C
erage mass, uniformity of mass, solubility in water, pH, moisture Sifting Area Humidity Not more than 50%
content, assay and microbial limit test of granules. Frequency of Recording Initial and every one hour interval
Sieve Used Sieve Size and Sieve Integrity
Operation
Dispensing details Table 5

Operation/Parameter Std. Specification Granulation details

Room Cleaning Should be clean

Pre-check For Granulation and Conditioning
Equipment Cleaning Should be clean
Operation/Parameter Std. Specification
Utensils Cleaning Should be clean
Room Cleaning Should be clean
Equipment Calibration Should be calibrated
Equipment Cleaning Should be clean
Temperature Not more than 250C
Equipment Calibration Should be calibrated
Humidity Not more than 60%
Area Temperature Not more than 250C
Material Dispensing Should complies to BOM
Area Humidity Not more than 60%
Table 4
Frequency of Recording Initial and every one hour
interval
Bill of materials (Bom)
Table 6
All the ingredients should be dispensed as per approved Bill of
Materials. Care should be taken to ensure that right materials are
being dispensed in right quantity.

Citation: Sayef Shahriad Ripon., et al. “Process Validation Protocol of Granules for Oral Administration”. Acta Scientific Pharmaceutical Sciences 3.12
(2019): 37-42.
Process Validation Protocol of Granules for Oral Administration

41

Stepwise batch manufacturing operation Yield reconciliation

Calculate the yield as per BMR and BPR and find out the maxi-
Std. Specification/
Sl. No. Step Instruction mum and minimum range.
Parameter
Stage I: Granulation
Step-1 Sieving Sieve Used Operation / Parameters Purpose
Before After Blending For Information only
Sieve Integrity
After After Filling For Information only
Step-2 Solvent PW Quantity
Table 8
Step-3 Dry mixing Impeller Speed
Mixing Time Stability
Step-4 Wet Mixing Impeller Speed Carry out the normal room temperature and accelerated tem-
Chopper Speed perature stability studies as per the stability protocol. This stability
Solvent Quantity shall be concurrent stability.
Mixing Time
Amperage Summary
Step-5 Drying in FBD Inlet Temperature Summary report and conclusion shall be prepared and ap-
Outlet Temperature proved based on the acceptance criteria and the data collected dur-
Total Drying Time ing Process Validation studies and all the results shall be verified
Step-6 Sizing Screen Used against acceptance criteria.
Before
Sieve Integrity Discrepancy and corrective action
After
Send the sample to QC for Report any discrepancy observed in the process or test result
Step-7 determination of moisture Moisture Content beyond the standard specification and mention what corrective
content. and preventive action is taken against the discrepancy.
Stage II: Blending
During the granules with Blender Speed Approval
Step-8
Blender Machine Blending Time Based on the results reported and summary in the validation
Send the sample to QC for reports, approve the process validation report as preliminary
Assay and blend
Step-9 determination of moisture
uniformity and final approval. Approval section should include; prepared by,
content.
checked by, verified by, approved by and authorized by signature
Stage IV: Packaging (Sachet Filling, Sealing and Packaging)
with date.
Step- Packaging (Sachet Filling, Filling Area
10 Sealing and Packaging) at Temperature
Lower speed, higher speed Filling Area RH Conclusion
and optimum speed with If validation is not done, product quality may vary from batch to
full, medium and low hop- Average Net Weight
batch of manufacturing. To avoid this limitation, process validation
per Machine Speed
activity poses a significant role in establishing documented evi-
Auger Speed
dence to ensure consistent quality product meeting its controlled
Auger Count
specification. The outcome of this paper is to focus the importance
Sachet Sealing
Temperature [Bottom] and stepwise procedure for conducting process validation through
Sachet Sealing an approved validation protocol.
Temperature [Vertical]
Sachet Sealing Bibliography
Temperature [Top] 1. EU Guidelines for Good Manufacturing Practice for Medicinal
Leak Test
Products for Human and Veterinary Use; Ares 4 (2015).
Quality Of Batch Printing
Packing Area 2. Comparative Framework Between New Product and Legacy
Temperature
Product Process Validation-Mark Mitchell, Pharmatech Asso-
Packing Area RH
ciates, Inc.
Table 7

Citation: Sayef Shahriad Ripon., et al. “Process Validation Protocol of Granules for Oral Administration”. Acta Scientific Pharmaceutical Sciences 3.12
(2019): 37-42.
Process Validation Protocol of Granules for Oral Administration

42

3. FDA Guidance for Industry; Process Validation: General Prin-

ciples and Practices; Revision-1 (2011).

4. General guidance on hold‑time studies, WHO Technical Report

Series Annex4 (2015): 992.

5. Guide to Good Manufacturing Practice for Medicinal Products

Part II, © Pic/S (2018).

Volume 3 Issue 12 December 2019

© All rights are reserved by Sayef Shahriad Ripon., et al.

Citation: Sayef Shahriad Ripon., et al. “Process Validation Protocol of Granules for Oral Administration”. Acta Scientific Pharmaceutical Sciences 3.12
(2019): 37-42.